Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons

Sabrina M Heman-Ackah; Raquel Manzano; Jeroen J M Hoozemans; Wiep Scheper; Rowan Flynn; Wilfried Haerty; Sally A Cowley; Andrew R Bassett; Matthew J A Wood

doi:10.1093/hmg/ddx331

Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons

Hum Mol Genet. 2017 Nov 15;26(22):4441-4450. doi: 10.1093/hmg/ddx331.

Authors

Sabrina M Heman-Ackah^{1

2

3}, Raquel Manzano⁴, Jeroen J M Hoozemans⁵, Wiep Scheper^{6

7}, Rowan Flynn⁸, Wilfried Haerty⁹, Sally A Cowley⁸, Andrew R Bassett¹⁰, Matthew J A Wood⁴

Affiliations

¹ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
² NIH Oxford-Cambridge Scholars Program, National Institutes of Health, Bethesda, MD 20892, USA.
³ UNC MD-PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
⁵ Department of Pathology, Neuroscience Campus Amsterdam.
⁶ Department of Clinical Genetics and Alzheimer Center, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
⁷ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, 1081 HV Amsterdam, The Netherlands.
⁸ James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
⁹ Earlham Institute, Norwich Research Park, Norwich NR4 7UH, UK.
¹⁰ Genome Engineering Oxford, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Abstract

The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1α is expressed in PD brains within neurons containing elevated levels of α-synuclein or Lewy bodies. Having used this pair of isogenic iPSCs to define this phenotype, these cells can be further applied in UPR-targeted drug discovery towards the development of disease-modifying therapeutics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Duplication
Gene Expression
Gene Expression Profiling
Humans
Induced Pluripotent Stem Cells / metabolism
Induced Pluripotent Stem Cells / pathology
Induced Pluripotent Stem Cells / physiology*
Lewy Bodies / pathology
Mutagenesis, Site-Directed
Neurons / metabolism
Parkinson Disease / genetics*
Parkinson Disease / metabolism
Parkinson Disease / pathology*
Unfolded Protein Response
alpha-Synuclein / genetics*
alpha-Synuclein / metabolism

Substances

SNCA protein, human
alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding